Introduction to Pharmacology for APRNs Nursing CE Course

asses of medications, understand how medications work, recognize both the generic and brand name of medications, follow the restrictions regarding controlled substances, be familiar with credible resources to obtain specific information about medications (e.g., drug handbooks, online resources), and ensure patients are adequately educated on all medications. APRNs must ascertain a comprehensive understanding of drugs and their effects on the body to determine whether the intended medication effects have been achieved and recognize unintended effects (Smith & Pacitti, 2020).

Pharmacology

Pharmacology is the study of chemicals (i.e., drugs) used to prevent, diagnose, or treat disease and their effects on the body. Pharmacology analyzes the actions of drugs, incorporating knowledge from two primary and interrelated domains: pharmacokinetics and pharmacodynamics. A drug can have three effects on the body:

• therapeutic effect (the intended, positive influence on the body)
  • e.g., diphenhydramine (Benadryl) administered to alleviate pruritus, swelling, and erythema caused by a bee sting
• side effect (a non-therapeutic effect on the body)
  • e.g., diphenhydramine (Benadryl) administered to alleviate pruritus, swelling, and erythema caused by a bee sting, also leading to side effects of drowsiness and sedation
• adverse effect (a negative, undesirable, unintended, or harmful consequence to the body)
  • e.g., diphenhydramine (Benadryl) administered to alleviate pruritus, swelling, and erythema caused by a bee sting inadvertently inducing hypotension and syncope in an elderly patient (Katzung, 2018)

The goal of medication therapy is to achieve a desired beneficial effect with minimal adverse effect or toxicity. When administered for therapeutic purposes, drugs are often referred to as medications since the intent is to elicit a specific response. In most clinical settings, these terms are used interchangeably and carry the same meaning. All prescribed medications have two names: the generic name and the brand (or trade) name. An example of a generic name is acetaminophen, and its corresponding brand name is Tylenol. A generic name typically begins with a lower-case letter, whereas the first letter of a brand name is capitalized (e.g., acetaminophen [Tylenol]). A generic drug may have multiple brand names, such as the non-steroidal anti-inflammatory drug (NSAID) ibuprofen, sold under the brand names Motrin and Advil. Due to the wide variability in brand names, best-practice guidelines recommend that generic names prevent confusion. For this education module, both generic and brand names will be utilized when referencing medications (Smith & Pacetti, 2020).

Drug Development

The US Food & Drug Administration (FDA) regulates the safety and efficacy of all drugs (prescription and over-the-counter [OTC]) sold in the US. All drugs are toxic to some individuals at some dose. For a manufacturer to obtain FDA approval of a new drug, they must demonstrate the drug’s safety and effectiveness according to specified criteria outlined in federal law and the FDA regulations. In addition, the drug must pass FDA inspection and obtain approval for its labeling (i.e., all written material about the drug, including its packaging, prescribing information for physicians, and patient brochures). The drug’s safety, dosing, and usefulness in treating disease are established through rigorous laboratory research, in vitro studies, and clinical trials involving human participants. Clinical trials for drug development have four primary phases (see Figure 1). Phase I evaluates the drug’s safety in humans and typically involves a few (usually 20 to 80), healthy adult volunteers, although there are exceptions, such as anti-cancer therapies. Phase II assesses the drug’s effectiveness in treating disease, starts to evaluate the drug in the target population, and establishes the final dosage. Phase III tests the drug on a larger scale of human participants (e.g., up to 3,000) and brings the drug to market. Phase III studies are typically operationalized with randomized control trials. The drug’s clinical utility is tested against another drug or placebo to ensure the drug is safe and effective in the target population and disease entity. Phase IV consists of post-marketing trials, such as when the manufacturer is trying to get the drug approved for another indication. Once a drug is on the market, the FDA maintains oversight of the drug’s long-term safety and effectiveness and can remove the drug from the market if necessary (Dabrowska & Thaul, 2018; FDA, 2018c; Katzung, 2018).

Prescription Medications, Herbals, and Dietary Supplements

Drugs are either prescribed (obtainable only by prescription from a licensed provider) or available OTC without a prescription. OTC agents are readily available and can be purchased at a store or online, including herbal preparations and dietary supplements. Patients use these agents for diverse indications, such as to manage symptoms or enhance wellness. Some prescription medications are available for purchase as OTC preparations in smaller doses. For example, ibuprofen (Motrin) is available OTC in 200 mg doses, whereas the prescription strength is 800 mg. Diphenhydramine (Benadryl) is available OTC in 25 mg doses, and the prescribed strength is 50 mg. While the FDA regulates prescription and OTC medications to ensure their safety and efficacy, herbal preparations and dietary supplements are not subjected to the same scrutiny and oversight. Herbs and supplements represent various substances ranging from vitamins and minerals to enzymes, probiotics, and botanicals. Dietary supplements are available in an array of forms, such as pills, gummies, powders, energy bars, and drinks. Supplements like protein powders are commonly marketed to athletes to enhance muscle mass and performance but contain many hidden components that may not be appropriate for all consumers. Furthermore, most supplements and herbal preparations have not undergone rigorous scientific testing for safety or effectiveness. The lack of FDA oversight and regulation of these agents poses concerns regarding their consistency, ingredient purity, and safety profiles. Although patients do not require a prescription to obtain these substances, they still pose a risk for adverse effects and dangerous interactions (Katzung, 2018; National Center for Complementary and Integrative Health [NCCIH], 2019; National Institute on Aging, 2021). 

    For more information on this topic, refer to the Dietary Supplements NursingCE course.

Drug Classification

Drugs are grouped according to their similarities. A drug can be classified by its chemical composition, effect on a specific body system, or ability to treat a particular disease. The overall purpose of drug classification is to ensure patient safety and guide provider selection. Table 1 provides a few examples of prescription drug classifications based on chemical makeup and the intended mechanism of action. While there are numerous drug categories (which extend beyond the scope of this module), many drugs fit into multiple categories because they exert various effects on numerous body systems (Ernstmeyer & Christman, 2020; Katzung, 2018; Lilley et al., 2017).

Pharmaceutics

Pharmaceutics refers to the process of drug formulation and manufacturing. To understand the actions of drugs on the body and what happens to the drug in the body, it is first essential to understand drug composition and formulation. A drug's ability to dissolve in the body primarily depends on its form. Drugs can be administered in 3 ways: enterally, parentally, and topically. Parenteral forms bypass the gastrointestinal (GI) tract and are administered intradermally, intramuscularly, subcutaneously, or intravenously (see Figure 2). Parenteral forms allow for immediate absorption since they avert the body’s need to dissolve the drug. Topical preparations are administered via aerosol, cream, foam, gel, suppository, and patches. These drugs may act directly on or be absorbed through the skin for a systemic response. Enteral forms are given via the intestinal tract through the mouth, the rectum, or direct instillation into the intestine by a catheter device (i.e., nasogastric [NG] tube; Katzung, 2018; Le, 2020; Lilley et al., 2017).

Drugs may be chemically formulated to have an effect over a specific period. Modified-release preparations have altered the timing or the rate of release of the medication to the body. In contrast, immediate-release (IR) dosage forms release the drug upon contact with the GI tract. Modified-release drugs may have a delayed (delayed-release [DR]) or a prolonged (extended-release [ER]) effect. With DR formulations, an initial amount may be released immediately after administration; the most common example is enteric-coated acetylsalicylic acid (Aspirin), which delays absorption until after the medication passes through gastric acids. ER preparations release the drug over a prolonged period and consist of sustained-release (SR) and controlled-release (CR), but may also be abbreviated as XR, XL, or XT. SR delivers the drug over a sustained period to maintain steady drug concentration levels in the body, but not at a constant rate. CR maintains drug release over a sustained period at a nearly fixed rate. APRNs must be cognizant of the formulation they are prescribing because ER medications are dosed less frequently due to their slow release over time. Orally disintegrating tablets (ODT) break apart rapidly upon contact with the saliva and may be used without water. The drug is dispersed in saliva and swallowed with little or no water. There is no industry standard for these modified-release dosing abbreviations and acronyms, and there may be multiple abbreviations for each indication (see Table 2). Therefore, confusion and misreading have caused prescribing errors. This has been mitigated, to some extent, with the advent of electronic health records (EHRs) and electronic medication prescribing (e-scribe) programs (Katzung, 2018; Le, 2020; Lilley et al., 2017; Shargel & Yu, 2016).  

Pharmacokinetics and Pharmacodynamics

Pharmacokinetics (what the body does to a drug) refers to the movement of a drug through the body and the series of biochemical processes it undergoes. Pharmacodynamics (what a drug does to the body) studies how drugs act at target sites of action in the body, as summarized in Figure 3 (Katzung, 2018).

Pharmacokinetics

Pharmacokinetics includes four primary stages that drugs undergo: absorption, distribution, metabolism, and excretion (abbreviated as ADME, see Figure 4). These stages will be outlined in this section (Katzung, 2018; Lilley et al., 2017). 

Absorption

For a drug to produce its intended effect(s), it needs to enter the body and reach its primary action site. Absorption requires the transmission of a drug from its administration site to the body's circulation. Factors that determine drug absorption include its biochemical properties, formulation, and route of administration. While drugs are available in various forms, all drugs must be liquefied (i.e., dissolved into a solution) to be absorbed by the body. Thus, the body more rapidly absorbs liquid formulations than the same agent in pill (i.e., tablet or capsule) form, which needs to disintegrate before absorption can occur. Unless administered intravenously, all drugs must cross several semipermeable cell membranes to reach systemic circulation and gain access to their target site. Cell membranes are biological barriers that selectively inhibit the passage of drug molecules. Drugs cross these barriers by passive diffusion, facilitated passive diffusion, or active transport (see Table 3 and Figure 5; Katzung, 2018; Le, 2020).

Some agents have an enteric coating or a polymer applied to their exterior to delay dissolution until they reach the intestines. Without this coating, the acidic pH of the stomach would break down the chemical composition of a drug, rendering it ineffective. Enteric-coated pills should never be crushed because their action may be lost before leaving the stomach. There are various oral formulations of medications, each of which has variable absorption rates, as illustrated in Table 4 (Katzung, 2018; Lilley et al., 2017).

The medication administration route also has a strong influence over the absorption process as follows (Katzung, 2018; Lilley et al., 2017; Smith & Pacitti, 2020):

• Oral drugs (i.e., swallowing a pill) must pass through a layer of epithelial cells that line the GI tract. The absorptive pattern of drugs administered orally varies due to the solubility and stability of the drug, the pH of the GI tract and its motility, the presence of food in the stomach or intestines, concomitant drugs or supplements, and its formulation (see Table 4).
• Sublingual and buccal drugs are placed under the tongue (sublingual) or between the gums and the cheek (buccal) and are rapidly absorbed before swallowing. This route prevents the gastric pH from inactivating the medication and optimizes absorption through the highly vascular mucous membranes. 
• Rectal and vaginal drugs (e.g., inserting a rectal or vaginal suppository) are easily absorbed and can precipitate both local and systemic effects. However, the presence of stool in the rectum or discharge in the vagina can limit tissue contact with the medication and hinder absorption. Many vaginal suppositories (e.g., estradiol [Vagifem] tablet) are primarily used for their local effects on the vaginal mucosa and limited systemic absorption.
• Inhaled drugs (i.e., breathing a medication from an inhaler or nebulizer) through the mouth or nose are rapidly absorbed through capillary networks in the nose or lung alveoli.
• Transdermal drugs (i.e., applying a patch to intact skin) allow for slow, gradual absorption. The effects of transdermal drugs can be local (e.g., lidocaine [Lidoderm] patch) or systemic (e.g., fentanyl [Duragesic] patch).
• Subcutaneous (i.e., injecting into fat tissue) and intramuscular drugs (i.e., injecting into a muscle) may be absorbed quickly or slowly. For example, water-soluble drugs (e.g., insulin) are absorbed rapidly, whereas less water-soluble agents (e.g., leuprolide acetate [Lupron]) have a slower absorption rate. In general, drugs given intramuscularly are absorbed relatively quickly due to the high vascularity of muscles; however, patients with poor peripheral perfusion may experience delayed absorption. 
• Intravenous (IV) drugs (i.e., infusing through a venous access device) are absorbed the most rapidly and entirely of all routes. This is because IV drugs are transmitted directly into the bloodstream, do not need to be broken down, and reach tissues in their original chemical form. 

Distribution

Distribution is the transportation of drugs to sites of action by bodily fluids. Once a drug enters systemic circulation, it needs to be dispersed into interstitial and intracellular fluids to reach its target. Drugs are primarily designed to bind to a receptor site to induce or thwart a specific action predictably; however, secondary side effects occur when the drug binds to other sites in addition to the target. Due to their high vascularity and extensive blood supply, the heart, liver, kidneys, and brain are the most common organs exposed to the drug first. Many drugs are considered potentially hepatotoxic (i.e., can cause liver injury) or nephrotoxic (i.e., can cause kidney injury) because they pass through these organs in higher concentrations, increasing their potential to cause damage. Drug distribution depends on the following factors (Katzung, 2018; Lilley et al., 2017; Smith & Pacitti, 2020):

• Circulation can either enhance or inhibit the perfusion of drugs throughout the body.  Health alterations such as cardiovascular disease or peripheral vascular disease can cause poor circulation and delay medication distribution. Hydration status (i.e., dehydration and overhydration) can impact circulation and affect the drug's ability to perfuse in the intended manner.
• Permeability of cell membranes is another factor that affects drug perfusion through the body. As described earlier, drugs must pass through several cell membranes before they reach their target tissue. Oral drugs must pass through cell membranes in the GI tract and capillaries to enter the circulation and then leave the circulation to bind with receptors on target cells. They subsequently return to circulation and pass through the liver. A certain amount of the drug is metabolized by liver enzymes (i.e., first-pass effect) and re-enters circulation before being excreted by the body.
• The blood-brain barrier and the placental barrier protect the brain and the developing fetus, respectively, from potentially dangerous substances, such as poisons or viruses. As demonstrated in Figure 6, the blood-brain barrier is a blockade of tightly interwoven capillaries that prevent the passage of most drugs. Only certain medications comprised of lipids or attached to a carrier molecule can pass through this barrier. The placental barrier is more permeable than the blood-brain barrier; while some drugs can harm a fetus, many have not been studied in pregnant patients. 
• Plasma protein-binding sites affect the distribution of drugs within the bloodstream. A certain percentage of most drugs is bound to plasma proteins upon entering the bloodstream, forming a drug-protein complex. Their distribution is affected by how much of the medication is given, the plasma protein level in the blood, and the medication’s transport to target tissues. The drug-protein complex is usually too large to pass through the capillaries into tissues; only unbound or "free" amounts of the drug are pharmacologically active and can exert a therapeutic effect. The portion of the drug that is "protein-bound" remains inactive while bound, whereas the part that escapes the initial protein binding is immediately "free" to bind to the target tissue. Patients with diminished protein stores, such as those who are malnourished or have underlying liver disease, are at higher risk for drug toxicity. Diminished protein stores increase the amount of free drug; thus, these patients typically require lower drug dosages to prevent toxicity. 
• In addition to the examples cited above, several disease states can alter drug distribution or cause drug-disease interactions as follows:
  • Obesity allows for greater accumulation of lipid-soluble agents within the patient's adipose tissue, increasing their distribution and extending their half-life.
  • Pregnancy increases the patient’s intravascular volume.
  • Edema or an edematous state (e.g., heart failure, cirrhosis, nephrotic syndrome) prolongs distribution, increases half-life, and delays drug clearance.

Metabolism

Metabolism is the chemical alteration of a drug by the body. Once a drug has been absorbed and distributed, the metabolism (i.e., breakdown) of the drug molecule ensues. Through enzyme activity and chemical reactions, drugs are dissolved into their less-active or inactive forms called metabolites. Metabolism occurs primarily in the liver through the action of enzymes, but limited metabolism can also occur in the kidneys, lungs, intestines, and blood. Cytochrome P450 (CYP) enzymes are primarily capable of and responsible for metabolizing most drugs, toxins, and normal cellular components. They also serve a chief role in synthesizing essential endogenous substances in the body, such as hormones, steroids, and fatty acids. Most drugs are lipid-soluble, and the kidneys can only excrete water-soluble substances. Therefore, the liver must convert lipid-soluble drugs to water-soluble substances as they pass through the liver to allow easier excretion via the urine. Several factors affecting drug metabolism are outlined below (Carpenter et al., 2019; Katzung, 2018; Lilley et al., 2017; Smith & Pacitti, 2020):

• Age is an important consideration that can widely affect the metabolism of a drug. Infants have a limited capacity to metabolize medications because the liver is still developing, and enzymes are not fully generated. Metabolism also tends to decline with age, and older adults frequently require a dosage reduction to avoid hepatic toxicity. 
• Increased medication-metabolizing enzymes can cause a drug to be metabolized faster than anticipated. This phenomenon can result from receiving the same drug over an extended period and may warrant an increase in dosage to maintain a therapeutic level or a change in drug therapy. An increase in medication-metabolizing enzymes can also elevate the metabolism of other drugs being administered concurrently.
• The first-pass effect (or first-pass hepatic metabolism) is a common phenomenon with oral drugs. As the liver enzymes break down the drug, some of it escapes into the general circulation and becomes protein-bound or free. Several doses are typically required before enough free drug stays active in the circulation to exert its desired effect. Examples of drugs that undergo a significant first-pass effect include morphine sulfate (MS Contin), propranolol (Inderal), diazepam (Valium), and midazolam (Versed). Drugs inactivated by the liver need to be given by a route not involving the GI tract (i.e., parenteral route). There is wide variability regarding the extent to which each patient experiences the first-pass effect, making it an unpredictable phenomenon. For drugs that undergo considerable first-pass metabolism, monitoring the blood levels of these drugs is the most viable way to maintain a therapeutic concentration. 
• Similar metabolic pathways can alter the metabolism of two drugs administered concurrently. The rate of metabolism can decrease for either or both drugs, leading to toxicity. An example of this is the commonly used anticoagulant coumadin (Warfarin) and two widely utilized cholesterol-lowering medications known as statins (e.g., rosuvastatin [Crestor] or simvastatin [Zocor]). Rosuvastatin (Crestor) and simvastatin (Zocor) inhibit warfarin (Coumadin) metabolism by a specific metabolic pathway (i.e., CYP2C9), generating increased concentrations of warfarin (Coumadin) and heightening bleeding risk.
• Nutritional status also impacts drug metabolism. Since nutritional status alters drug distribution and plasma protein binding sites, malnourished patients with limited protein stores have an increased risk of drug toxicity due to the reduced availability of metabolizing enzymes.

Excretion 

Excretion is the process by which the body eliminates waste (including drug metabolites). As the kidneys filter the blood, they screen the excess free metabolites; a portion is reabsorbed into the bloodstream, and the remainder is excreted through the urine. Renal excretion is supported by glomerular filtration, active tubular reabsorption, and active tubular secretion. The free or unbound water-soluble form of a drug or metabolite enters the kidney through passive glomerular filtration. The vasculature surrounding the nephron may also help transport metabolites into the nephron via tubular secretion. Active reabsorption can pull some of a drug back into circulation and redistribute it throughout the body. Kidney dysfunction can impair the body’s ability to eliminate a medication adequately, leading to increased circulating levels and consequential toxicity. Kidney function is most commonly measured through serum laboratory values (i.e., creatinine [Cr], glomerular filtration rate [GFR], blood urea nitrogen [BUN], and creatinine clearance [CrCl]). The GFR is the best indicator of kidney function and is often used as a surrogate for CrCl when dosing medications in clinical practice. These levels need to be monitored closely for patients with underlying kidney dysfunction, acute kidney injury, or chronic renal disease when prescribing medications. While the primary site of excretion is through the kidneys, this process can also occur via the liver (i.e., excretion of byproducts and waste into bile), lungs (i.e., exhalation of gases and alcohol), intestines (i.e., feces), and exocrine glands (i.e., sweat). Biliary excretion permits the excretion of a drug through the GI tract via feces (Katzung, 2018; Lilley et al., 2017; Smith & Pacitti, 2020).

Core Elements of Drug Dosing

Dosing considerations are essential to understanding the effect drugs can have on a patient. The APRN must pay close attention to the anticipated effect, patient response, and safe dose range for each agent when prescribing medications. The APRN must be aware of the overall dose-response based on the prescribed dosage. As the dose of the drug increases, the response should increase. Every drug has an onset, peak, and duration of efficacy. The onset of action is influenced by the route of administration, functional capacity of the GI tract, and patency of the circulatory system. The peak refers to the maximum concentration (Cmax), typically where the patient demonstrates the most significant therapeutic effect. The duration of efficacy refers to the length of time the medication yields its desired therapeutic effect. Every drug has a minimally effective dose (minimal effective concentration [MEC]) and a minimally toxic dose (minimal toxic concentration [MTC]). The therapeutic window lies between the MEC and the MTC and represents the range of the safest and most effective treatment (see Figure 7) or the ideal plasma drug concentration (Cp). Since it is not feasible to determine the amount of a drug that reaches its target site of action after administration, the Cp is measured. An example of this concept is warfarin (Coumadin), commonly prescribed to prevent blood clotting. Optimal warfarin (Coumadin) drug levels are monitored with a blood test called the international normalized ratio (INR). If the dose of warfarin (Coumadin) is too high, the INR increases above the therapeutic window, heightening the risk of bleeding (i.e., a toxic drug effect). In contrast, if the dose of warfarin (Coumadin) is too low, the INR level declines below the therapeutic window, reducing the drug’s efficacy, and increasing the risk of blood clotting. Therefore, APRNs must monitor the INR levels of patients receiving warfarin (Coumadin) to ensure the dosage appropriately reaches the therapeutic window without increasing the risk of harm. Patients on warfarin (Coumadin) often require periodic dosage adjustments based on their INR level (Katzung, 2018; Longo, 2019).

Unless a drug is administered by continuous infusion, variations in concentration will depend on its dosing frequency. The drug's half-life and the body’s ability to metabolize or excrete the drug determine the trough concentration. Therapeutic drug monitoring with peak and trough levels is performed to adjust drug doses based on the Cp at defined intervals. The goal is to prevent and manage an undesirable overdose or under-dose. If the peak level is too high, the patient is at risk of drug toxicity. If the peak level is too low, the patient is at risk of receiving a non-therapeutic dose of the drug, mitigating its intended effect. The trough level should be collected just before the next dose is administered. For example, Gentamycin (Garamycin), an aminoglycoside antibiotic, must maintain plasma concentration at a steady state (Cpss) to treat the underlying infection for which it has been prescribed. However, gentamycin (Garamycin) is also highly nephrotoxic and requires diligent monitoring of the peak level and renal function tests to ensure the dose is not reaching toxic levels. The prescriber is responsible for ensuring that peak and trough levels are monitored when indicated (Katzung, 2018; Lilley et al., 2017).

The body’s rate of excretion influences a medication’s duration of action. The area under the curve (AUC) represents the total drug exposure over time and is an essential parameter for both pharmacokinetic and pharmacodynamic analyses. It is based on the body’s elimination rate and the dose administered and reflects the optimal concentration of a specific drug in the body. The higher the AUC for a given dose, the lower the drug clearance. The AUC is clinically useful for monitoring drugs with a narrow therapeutic index, such as gentamycin (Garamycin) and phenytoin (Dilantin). Clinical trials can indicate whether two drug formulations of the same dosage (e.g., a 10 mg capsule and a 10 mg tablet) result in equal tissue or plasma exposure (Katzung, 2018; Lilley et al., 2017).

APRNs must be cognizant of the distinctions in dosing. A single dose is the recommended amount of a drug given at a single time (e.g., clarithromycin [Biaxin] ER may be dosed at 1,000 mg daily for certain low-risk adults with pneumonia). A course dose, or divided dose, is the recommended amount of a drug given over a defined period (e.g., pediatric pneumonia patients may be treated with amoxicillin [Amoxil] 90 mg/kg/day dosed BID or 45 mg/kg/day dosed TID). Specific high-risk drugs such as antineoplastic therapies (i.e., chemotherapy or radiation therapy) have cumulative dose restrictions. A cumulative dose refers to the total dose of the drug after repeated exposure to treatment, adding up each time the patient has received it. Some drug toxicities are more severe or more likely to occur as the cumulative dose of the drug increases. For example, the cumulative dose for doxorubicin (Adriamycin), a potent chemotherapy agent, is 550 mg/m2 (or 450 mg/m2 if the patient received prior radiation therapy to the chest) due to the heightened risk of cardiotoxicity. Tracking the cumulative dose of these agents is critical for patient health and safety. While some EHRs have features that automatically calculate and document the dosing of drugs, others lack such features and require APRNs to devise a metric for tracking and logging these doses (Olsen et al., 2019).

Drug Clearance and Half-Life 

Drug clearance refers to the overall process of eliminating drugs from the body. Drug clearance is among the most important pharmacokinetic parameters because it determines the maintenance dose rate (i.e., dose per unit of time) required to maintain the Cp of the drug. The half-life is when the drug has lost half its Cmax; this decline reflects how quickly and efficiently the drug is metabolized and excreted from the body. A drug's half-life is analogous to the concept of CrCl, which measures Cr (a waste product produced by muscles from the breakdown of a compound called creatinine) levels in the blood. The amount of Cr produced in the body depends on muscle mass and is relatively constant for each patient. The amount of Cr removed from the blood relies on the filtering capacity and functioning of the kidneys and the rate at which blood is carried to the kidneys. The same principle applies to drug clearance; however, unlike CrCl, the clearance of a drug is rarely measured directly. Instead, drug clearance is calculated as the volume of plasma that gets filtered of the drug per unit of time (volume/time). Typically, 4 to 5 half-lives are needed for the Cp to reduce to below 10% of the starting value, so drugs are considered excreted from the body when approximately 5 half-lives have occurred. If an additional dose of the drug is administered every half-life, 50% of the peak plasma is eliminated each half-life. Therefore, Cpss is achieved after 4 to 5 half-lives, regardless of whether the drug was given by constant IV Infusion or repeated intermittent doses. Drugs with a short half-life typically need to be administered several times per day, whereas drugs with a long half-life may only require once-daily administration. Since most drugs are metabolized in the liver and excreted by the kidneys, a decrease in the functioning of either of these organ systems can increase the half-life of a drug. Thus, patients with liver or kidney dysfunction may experience the toxic effects of drugs more easily. Many drugs require periodic lab monitoring of a patient’s liver (LFTs; i.e., alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase [ALP]), and kidney function (BUN and Cr; Katzung, 2018; Lilley et al., 2017).

Pharmacodynamics

Pharmacodynamics refers to the mechanisms and effects of medication on a person’s body. Pharmacodynamics studies the relationship between the drug’s concentration at the target site and its post-receptor effects, including therapeutic and adverse drug effects and interactions. For most drugs, the concentration at the receptor site determines the intensity of the drug’s effect. Understanding a drug’s mechanism of action (i.e., how it functions within a person’s body) is vital to comprehend the processes drugs endure to produce their intended effects. After a drug enters systemic circulation, it comes in contact with the cells of nearly all the body’s organs and tissues. The drug has to reach its target site (receptor) and bind to it to produce an effect. Receptors are specialized proteins found inside a cell or on a cell membrane located on various tissues (e.g., cardiac muscle, neurons in the central nervous system [CNS], GI tract). The joining or binding of a drug with a cell is called the drug-receptor interaction, creating a chemical bond between the receptor and the active site on the drug molecule (or substrate). When drugs bind to the receptor on a cell, they can alter its shape or activity, thereby changing its normal behavior. This relationship is often described as a “lock-and-key” model in which the substrate is the key that fits into the lock (i.e., the receptor), causing it to open (or activate) as demonstrated in Figure 8 (Katzung, 2018; Lilley et al., 2017).

A receptor is impacted by altering the cellular function, cellular environment, or enzymatic action. Drugs are classified into two categories (agonists or antagonists) based on their functional impact on the receptor. Drugs given to enhance a physiologic response are called agonists. A drug agonist binds tightly to a receptor, activating it to produce the desired effect. Morphine sulfate (MS Contin) is an example of an agonist because it binds with receptors to generate the desired effect of analgesia (i.e., pain reduction). Drugs given to block or lessen a typical response are called antagonists. Antagonists compete with other molecules to block a specific action at a receptor site and decrease the receptor’s ability to become activated by another agonist. Ranitidine (Zantac), a histamine-2 antagonist (H2 blocker), is an example of an antagonist. Ranitidine (Zantac) attaches to the H2 receptor on the parietal cells in the gastric mucosa to prevent the release of histamine-induced gastric acid (i.e., to treat or prevent heartburn or gastric ulcers). Figure 9 depicts drug agonists and antagonists (Katzung, 2018; Lilley et al., 2017).

Alterations in the cellular environment can also occur when a drug changes the structure of a cell, such as modifying the cell wall or revising a critical process (e.g., replication). For example, penicillin-type antibiotics (e.g., cephalosporins, monobactams, β-lactams, carbapenems) inhibit the cell wall synthesis of certain bacteria to destroy them. Sulfa-type antibiotics (i.e., sulfonamides and trimethoprim) inhibit bacterial replication by preventing folic acid synthesis, thereby disrupting DNA and RNA replication. Through a process called selective interaction, a drug can change a target molecule’s normal response by inhibiting or enhancing the action of an enzyme that affects the target molecule. For example, Angiotensin-converting-enzyme (ACE) inhibitors (e.g., lisinopril [Zestril], enalapril [Vasotec], benazepril [Lotensin]) block the activity of ACE, which is required to create the hormone angiotensin II. By blocking ACE, these medications decrease the production of angiotensin II, cause vasodilation, and reduce blood pressure, making it easier for the heart to pump blood to the rest of the body (Katzung, 2018; Lilley et al., 2017).

Interactions   

Drug-drug and drug-food interactions can dramatically change the action of a drug in a patient’s body. Precautions should be taken to limit or restrict certain types of food or the concurrent administration of interacting drugs. Interactions may increase or decrease the therapeutic effect of drugs, produce a new effect, or increase incidences of adverse effects. The simultaneous administration of 2 or more drugs can result in impaired excretion of the more slowly metabolized agent, prolonging or potentiating its effects. For example, when trimethoprim-sulfamethoxazole (Bactrim) is administered with warfarin (Coumadin), the antibiotic interferes with the metabolism of warfarin (Coumadin), increasing levels in the blood and heightening bleeding risk. Likewise, Simvastatin (Zocor) should not be administered with antifungal agents (e.g., fluconazole [Diflucan]), as the combination can lead to drug-induced hepatitis (inflammation of the liver) and rhabdomyolysis (the breakdown of skeletal muscles). Medications that are potent inhibitors of CYP450 enzymes (e.g., macrolide antibiotics and antifungals) are responsible for numerous drug-drug interactions. CYP450 inhibitors slow the metabolism and clearance of many drugs, thereby increasing drug concentration and heightening the risk of adverse effects, including drug overdose (Carpenter et al., 2019; Katzung, 2018; Lilley et al., 2017).

There are four primary mechanisms of drug-drug interactions: additivity, synergism, potentiation, and antagonism. Additivity, or an additive effect, occurs when the combined influence of 2 drugs is the sum of the expected individual responses (e.g., acetaminophen [Tylenol] combined with codeine sulfate [Codeine] can provide superior analgesia). An additive effect typically occurs when drugs work together positively. Still, this relationship can also induce unintentional harm, such as when ibuprofen (Motrin) is combined with acetylsalicylic acid (ASA). Since each agent can cause GI bleeding and gastric ulcers individually, this risk is significantly increased when they are taken together. In addition, a patient who ingests different CNS depressants, such as alcohol and opioids, can experience the combined effects of CNS depression (e.g., fatigue, sedation, impaired cognition, slowed reflexes, respiratory depression), which can be fatal. 

Another example of a harmful drug-drug interaction is the risk of serotonin syndrome with various antidepressant agents prescribed for major depressive disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, and social anxiety disorder. Serotonin syndrome results from the concurrent administration of selective serotonin reuptake inhibitors (SSRIs; citalopram [Celexa], escitalopram [Lexapro], fluoxetine [Prozac], paroxetine [Paxil], sertraline [Zoloft]), serotonin-norepinephrine reuptake inhibitors (SNRIs; duloxetine [Cymbalta], venlafaxine [Effexor], desvenlafaxine [Pristiq]), monoamine oxidase inhibitor (MAOIs; tranylcypromine [Parnate], phenelzine [Nardil], isocarboxazid [Marplan]), or any other drug that enhances serotonin neurotransmission. Serotonin syndrome is characterized by agitation, anxiety, confusion, a high fever, sweating, tremors, a lack of coordination, dangerous fluctuations in blood pressure, and a rapid heart rate. It is a potentially life-threatening condition for which patients must seek immediate medical attention, as it can progress to delirium and coma (Carpenter et al., 2019; Katzung, 2018; Lilley et al., 2017). MAOIs were the first type of antidepressant medications developed. They impair the metabolism of serotonin and block monoamine oxidase, an enzyme that breaks down excess tyramine in the body. Tyramine is an amino acid that helps regulate blood pressure, and it occurs naturally in the body and certain foods. Due to the risk for serious adverse effects, the use of MAOIs for the treatment of depression is generally reserved for patients who have failed all other options. MAOIs have dangerous drug and food interactions. In particular, patients should be advised to avoid foods containing high levels of tyramine, such as aged cheese (aged cheddar, swiss, parmesan, and blue cheeses); cured, smoked, or processed meats (pepperoni, salami, hotdogs, bologna, bacon, corned beef, smoked fish); pickled or fermented foods (sauerkraut, kimchi, tofu); broths and sauces (soy sauce, miso, and teriyaki); soybean products; and alcoholic beverages (beer, red wine, liquors; Hall-Flavin, 2018; Mayo Clinic, 2019).

A synergistic effect occurs when a drug is enhanced if it is administered alongside another drug. The most described example of a beneficial synergistic effect between drugs is the use of combined antibiotic therapy with an aminoglycoside (e.g., gentamicin [Gentacin]) and penicillin (e.g., penicillin G benzathine [Bicillin L-A]). Since penicillin is bactericidal, it destroys the bacterial cell wall, facilitating the intracellular uptake and transport of aminoglycosides into the cell, thereby enhancing the bactericidal effect. Without penicillin, there is little intracellular uptake of the aminoglycoside and a reduced response. To differentiate between additive and synergistic drug effects, consider simple mathematic equations where additive effects are represented as 2+2=4 or 5, and synergistic effects are 2+2=5 (Carpenter et al., 2019; Katzung, 2018; Lilley et al., 2017).

Antagonism, or an antagonistic effect, denotes the interaction of 2 or more drugs in which an agent lessens the action of the other. Thus, the effect of a drug is decreased or blocked if it is administered with another drug. For example, administering an antacid (e.g., famotidine [Pepcid]) with ciprofloxacin (Cipro) reduces the absorption of the antibiotic, thereby diminishing its efficacy in treating an underlying infection. The use of opioids and naloxone (Narcan) is another example; naloxone (Narcan) is administered to reverse the effects of opioids during an acute overdose (Carpenter et al., 2019; Katzung, 2018; Lilley et al., 2017). 

Potentiation, or a potentiated effect, occurs when two unrelated drugs are combined, resulting in the increased effect of only a single drug. For example, the simultaneous use of hydroxyzine (Vistaril) and morphine sulfate (MS Contin) increases the analgesic effect of morphine sulfate (MS Contin) but does not impact the therapeutic effect of the hydroxyzine (Vistaril). Similarly, adding fluoxetine (Prozac) to lisinopril (Zestril) can decrease the patient’s blood pressure after a steady state of fluoxetine (Prozac) is attained but does not further enhance the antidepressant effects (Carpenter et al., 2019; Katzung, 2018; Lilley et al., 2017).

Harmful drug interactions can also ensue when patients combine dietary supplements or OTC agents with prescribed drugs. Omega-3 fatty acid (fish oil, algae oil) is a dietary supplement used to prevent cardiovascular disease and reduce inflammation. Omega-3 fatty acids (fish oil, algae oil) can interact with anticoagulants such as warfarin (Coumadin), increasing bleeding risk and antihypertensive medications and causing severe hypotension (NCCIH, 2019). Hypericum perforatum (St. John’s wort) is a supplement with chemical properties similar to SSRIs and should not be combined with SSRIs, SNRIs, or any serotonin-modulating agent. Hypericum perforatum (St. John’s wort) can expedite or diminish the prescribed agent's metabolism, leading to reduced efficacy or higher toxicity. It is notorious for interacting with several other prescription drugs and can decrease the efficacy of variable medications, including cyclosporine (Neoral), digoxin (Lanoxin), oral contraceptives, and warfarin (Coumadin; NCCIH, 2019). Antacids and calcium supplements interfere with the absorption of thyroid hormone-replacement medications such as levothyroxine (Synthroid), making them less effective (Carpenter et al., 2019; Frandsen et al., 2018; Katzung, 2018; Lilley et al., 2017). 

Drug-food interactions occur when a drug is given with food that reduces its absorption or increases its toxicity. Among several well-cited drug-food interactions, the most common is the interaction between grapefruit (or grapefruit juice) and statins (i.e., atorvastatin [Lipitor], lovastatin [Mevacor], rosuvastatin [Crestor], simvastatin [Zocor]). Grapefruit contains a chemical that interferes with the body's ability to metabolize these medications and can significantly increase the blood levels of statins, leading to greater risks of hepatitis, liver failure, and rhabdomyolysis. Ingesting fruit or fruit juice within 2 hours of taking fexofenadine (Allegra), an OTC antihistamine, can inhibit its absorption and impair its ability to block histamine release. The dietary intake of dark green leafy vegetables, beef liver, and soybean-containing foods should remain consistent for patients taking warfarin (Coumadin). These foods contain high amounts of vitamin K, which diminishes the blood-thinning properties of warfarin (Coumadin), thereby lessening its therapeutic effects (Carpenter et al., 2019; Frandsen et al., 2018; Katzung, 2018; Lilley et al., 2017).

Side Effects, Adverse Effects, and Toxicity

Side effects, adverse effects, cumulative effects, and drug toxicity are undesirable results of medication administration. Every drug carries a risk for side effects due to its activity on the body. The most common side effects of diphenhydramine (Benadryl) include dry mouth and drowsiness, whereas the most common side effects of the antiemetic agent ondansetron (Zofran) include constipation and headaches. APRNs are responsible for ensuring patients are adequately educated on the potential side effects of prescribed drugs and their management. For example, a patient experiencing dry mouth from diphenhydramine (Benadryl) may benefit from mitigation strategies, such as sucking on sugar-free candy to stimulate saliva production or using a saliva substitute. A patient experiencing constipation from ondansetron (Zofran) should be counseled on preventing and treating constipation via increased dietary fiber, adequate oral hydration, exercise, and a stool softener and/or laxative as needed. Adverse effects are unexpected, are more severe than side effects, and can even occur at standard therapeutic dosages. All drugs produce some type of adverse effect in some populations, which can be mild to life-threatening. Adverse effects of diphenhydramine (Benadryl) in older adults can include confusion, incoordination, and dizziness. Adverse effects of ondansetron can consist of electrocardiogram (ECG) changes such as QT-interval prolongation (Frandsen et al., 2018; Katzung, 2018; Lilley et al., 2017).

Cumulative effects occur from the repeated administration of a drug, becoming more pronounced than those produced by the first dose. Cumulative effects happen when the body cannot metabolize and excrete a drug before the next dose is given. If the next dose is administered while some of the previous dose is still in the patient’s body, the drug accumulates. A cumulative drug effect may occur in liver or kidney disease since these organs are the primary sites of drug metabolism and excretion. This is a common phenomenon among older adults with decreased cardiac, liver, or kidney function. Chemotherapeutic agents carry a high risk for cumulative effects, such as bone marrow suppression, fatigue, and neuropathy; these effects worsen with each dose. The body’s hematologic system has a more challenging time recovering from repeated insults of cytotoxic treatments, thereby prolonging the time to bone marrow recovery (e.g., prolonged pancytopenia). Renal toxicity associated with aminoglycoside antibiotics (e.g., gentamycin [Gentacin]) occurs from drug accumulation in the kidneys with repeated doses. Drug toxicity most commonly occurs when drugs are prescribed in higher-than-recommended dosages; it can also arise from impaired drug excretion secondary to impaired metabolism or elimination mechanisms. If a toxic level is reached, the patient will experience severe and possibly fatal adverse effects. Drugs with a small margin of safety can rapidly accumulate to a toxic level; thus, patients receiving drugs with a small margin of safety need to have their serum drug level regularly drawn and be closely monitored for signs and symptoms of toxicity. The effects of drug toxicity may be irreversible and life-threatening. For example, if vancomycin (Vancocin) is administered in toxic quantities, the patient can experience permanent damage to cranial nerve VIII, resulting in hearing impairment or deafness. Acetaminophen (Tylenol) administered in doses greater than 4,000 mg per day can cause temporary or permanent liver damage. Acetaminophen (Tylenol) is a component of many medications, and APRNs must remain hypervigilant to all the medications a patient is receiving before prescribing drugs containing acetaminophen (Tylenol). A common example is oxycodone-acetaminophen (Percocet) 5/325 mg, which is an opioid medication that contains 5 mg of oxycodone (Roxicodone) and 325 mg of acetaminophen (Tylenol) per tablet (Frandsen et al., 2018; Katzung, 2018; Lilley et al., 2017).

Hypersensitivity Reactions and Anaphylaxis

A hypersensitivity reaction (HSR) is an allergic reaction mediated by immunoglobulin E (IgE) mast cell activation. It occurs when the immune system is overstimulated by a foreign substance and forms antibodies that cause an immune response. HSRs occur secondary to the administration of a drug that the body recognizes as foreign. HSRs can occur within minutes of the initial administration (immediate) or several hours after the drug was administered (delayed). They can also arise after subsequent administrations of the same agent (repeated exposure). HSR symptoms result from histamine release and can be localized or systemic. Localized HSRs are typically limited to venous inflammation (i.e., redness at the injection site) and dermatologic manifestations (i.e., hives or wheals). Systemic HSRs can cause generalized inflammation and swelling of tissues, increased mucous production, and bronchiole constriction in severe cases. Initial signs and symptoms of HSRs most commonly include hives, urticaria, pruritis, swelling, back pain, facial flushing, rhinitis, abdominal cramping, chills, and anxiety. However, symptoms may suddenly progress to life-threatening anaphylaxis and anaphylactic shock, which is an exaggerated response of the body's immune system to a drug that precipitates a massive release of histamine and other chemical mediators into the body. Symptoms of anaphylactic shock can occur almost immediately after exposure and include hypotension, difficulty breathing (e.g., wheezing, bronchospasm, stridor), angioedema (i.e., swelling of the oral cavity, lips, and/or tongue), orbital edema, and cardiac arrest (Nettina, 2019; Olsen et al., 2019).

The likelihood of HSRs can be reduced for high-risk drugs by pre-medicating patients with a combination of agents such as corticosteroids, antihistamines (e.g., diphenhydramine [Benadryl]), acetaminophen (Tylenol), and/or H2 blockers (e.g., famotidine [Pepcid]). Management of HSRs focuses on decreasing vascular permeability, increasing vasoconstriction of the peripheral veins, and inducing smooth muscle relaxation of the bronchioles. Mild to moderate HSRs can be treated with an antihistamine such as diphenhydramine (Benadryl). A patient in anaphylactic shock requires immediate medical attention, including cardiopulmonary support and rescue drugs to prevent fatality. The treatment of anaphylactic shock focuses on reestablishing and securing an airway, oxygen therapy, and the administration of epinephrine 0.1-0.5 mg (1:10,000 solution for adult patients) to treat hypotension and induce bronchodilation (i.e., dilate the respiratory bronchi) and diphenhydramine (Benadryl) to block the additional release of histamine. Corticosteroids are commonly administered to decrease vascular permeability, enhance the effects of epinephrine, and block inflammatory mediators circulating in the blood. APRNs prescribing high-risk medications by IV (e.g., chemotherapy, certain antibiotics, immunotherapy, immune modulators) should be familiar with their institution’s specific HSR protocols and policies and access their rapid response or code blue teams when needed (Nettina, 2019; Olsen et al., 2019).

APRNs must inquire about patient allergies to drugs before prescribing any agents. Even minor drug reactions are noteworthy. If a patient reports an allergy to a drug, the APRN should inquire about the type of reaction experienced and document this information in the medical record. Most institutions require that the patient’s identification wristband lists all known allergies at the time of admission. Some drugs demonstrate cross-sensitivity to another drug, especially among antibiotics. For example, patients who have an allergy to penicillin may have a cross-sensitivity to a cephalosporin antibiotic. Before prescribing medications, APRNs must verify the patient’s allergies and confirm the absence of any medications that may cause a cross-sensitivity reaction (Burchum & Rosenthal, 2019; Carpenter et al., 2019; Katzung, 2018).

Drug Tolerance, Dependence, Abuse, and Misuse

APRNs must understand the distinctions between physiological and behavioral adaptations to medication therapy, such as tolerance, dependence, and addiction, as there are many misconceptions related to these concepts. Drug tolerance is the body’s decrease in response to a drug it receives over time. For the drug to continue to exert its desired therapeutic effects, the dosage must be increased. Tolerance is not synonymous with addiction. The National Institute on Drug Abuse (NIDA, 2020) defines drug tolerance to medication as the gradual need for an increased dose of a particular medication to obtain a similar effect. Tolerance development varies significantly from individual to individual and from medication to medication. Tolerance is due to the body's ability to adapt to its environment physically and is not limited to pain medication or illicit drugs. A patient can develop tolerance to a drug and not be addicted. However, if the patient continues to take the drug in increasing doses over a longer than the recommended period, addiction can occur with specific drugs.  Addiction is a combination of physical dependence and compulsive drug-seeking behaviors despite significant negative repercussions from use. Addiction is a chronic, neurobiological disease that has contributing genetic, psychosocial, physical, and environmental influences (Katzung, 2018; NIDA, 2020).

Physical dependence is the body’s physiological adaptation to a drug that develops with consistent and regular use. Physical dependence is also a component of addiction. The medication becomes necessary for normal body functioning and homeostasis and is typically accompanied by the negative symptoms of withdrawal when the medication is no longer present in the body. Misuse of prescription drugs is the ingestion or utilization of these medications in a manner, at a dose, or by an individual other than prescribed. This includes taking (stealing) another person’s medication or using pain medication to induce feelings of euphoria instead of alleviating somatic pain. The medical terms substance abuse and substance dependence have been replaced in recent years by substance use disorder (SUD). SUD may refer to an individual who has become addicted to nicotine, alcohol, prescription medications, or illicit drugs (NIDA, 2020). In another phenomenon called pseudoaddiction, the individual becomes intensely fearful of being in pain. This is common in postoperative patients and usually manifests as clock-watching, asking to be awoken to receive pain medication, and hypervigilance in documenting and monitoring pain medications. Pseudoaddiction usually resolves with effective pain management treatments and the decline of painful stimuli (in a postoperative patient, this involves the healing of the surgical site). Psychological dependence occurs when medication ingestion becomes associated with alleviating discomfort, such as pain, anxiety, depression, etc. The presence of the drug then becomes a calming and reassuring presence in the patient’s life, similar to a comfort or security object (Hudspeth, 2016a, 2016b).

The three categories of controlled substances that are most commonly misused or abused include opioids, sedatives/anxiolytics, and stimulants. These medications can only be administered with a valid prescription or licensed prescriber's order. Controlled substances are categorized by schedule (Schedules I-V) based on their therapeutic use, perceived risk of addiction, and potential for abuse as outlined by the US Drug Enforcement Administration (DEA; see Table 5).  Approximately 20% of people who require pain relief for acute pain (e.g., postoperative pain or chronic pain related to a health issue) are prescribed opioids. Opioids are narcotics and have addictive properties. They are safe if taken over a short period; however, if taken for extended periods or in higher-than-prescribed amounts, a patient has a significant risk of addiction (DEA, n.d.; Katzung, 2018; NIDA, 2020).

APRNs must monitor for signs of tolerance if a medication is prescribed over an extended period or if the specified amount of medication is no longer managing the underlying issue. In light of the ongoing opioid epidemic across the US, providing adequate pain management without promoting an opioid use disorder remains a significant challenge. Safer alternatives should always be explored and attempted before initiating a controlled substance if those alternatives exist. APRNs have been professionally trained to prescribe medications effectively and safely to treat and manage medical conditions within an overall treatment plan. However, the unique risks associated with controlled substances, their use, and potential drug interactions are significant (Hudspeth, 2016a, 2016b; Katzung, 2018; NIDA, 2020).

APRNs must uphold several responsibilities when providing safe, effective care for patients receiving opioids. State laws, regulations, and policies delineate prescriber responsibilities regarding the prescribing and dispensing of controlled substances. The US Department of Health and Human Services (2017) increased grant funding for developing novel strategies to impede this growing and deadly problem. These efforts have brought a new level of urgency to the matter, with heightened surveillance, restriction, and patient monitoring on long-term opioid therapy. Prescribers must be registered with the DEA, be granted prescriptive authority, and know the legislation regarding the prescribing and monitoring of opioids in the governing state. It is equally imperative for healthcare professionals to remain vigilant in screening for the signs and symptoms of misuse and abuse (Schiller & Mechanic, 2020). As part of the national movement to mitigate the opioid epidemic, most states (49 states, Washington DC, and Guam) have established statewide electronic databases or prescription drug-monitoring programs (PDMPs) to track and monitor opioid prescriptions. A PDMP is a statewide electronic database that collects designated data on controlled substances dispensed to or for each patient. The intent is to improve opioid prescribing, inform clinical practice, and protect patients at high risk. PDMPs are housed and operated by state regulatory, administrative, or law enforcement agencies. The housing agency disseminates information from the database to individuals authorized under state law to receive the information for purposes identified by state law. States arrange individual systems to track and monitor prescriptions. The details about use, access, and drug inclusion, as well as the regulations and implications for prescribers, vary from state to state. Most states have a method by which prescribers can access their patient's records in other or neighboring states. The key to the efficacy of PDMP systems is the mandate that all providers check the system before initiating opioid therapy. Reviewing each patient's history of controlled substance prescriptions using the PDMP database helps determine whether a patient is already receiving opioids or potentially dangerous combinations that place them at risk for overdose. Differences exist between states regarding how frequently providers should monitor this system and which controlled substances are included. Reporting systems help reduce the diversion of illegitimate opiate prescriptions (Centers for Disease Control and Prevention [CDC], 2020). The consistent and diligent review of best practices and the most recent evidence in pharmacology are necessary components of a safe and effective medical practice. APRNs are encouraged to remain aware of best practice prescribing guidelines, seek continuing education hours to stay informed, and ensure familiarity with prescribing guidelines and federal and state laws (Hudspeth, 2016a, 2016b).

For more information on the safe and effective prescribing of controlled substances, refer to the following NursingCE courses:

• Substance Abuse and Addiction for APRNs 
• Safe and Effective Prescribing of Controlled Substances for APRNs
• 3-Part Pain Management Series for APRNs  

Considerations, Precautions, and Special Populations

Certain drugs should only be given after careful consideration of the underlying precautions or avoided entirely. Patients with underlying medical conditions, those of a specific age group, and pregnant or lactating women are considered special populations. APRNs must know contraindications if a disease state or patient characteristic renders a drug inappropriate for use due to the potential for adverse effects. For example, tobacco users should use oral contraceptives cautiously due to the heightened risk of vascular events (i.e., venous thromboembolism [VTE]). Tamoxifen (Soltamax) should be used with caution by women who have a history of VTEs, such as deep vein thrombosis (DVT) or pulmonary embolism (PE), due to the combination’s increased risk for blood clotting. Bisphosphonates are the most widely used medications for treating osteoporosis, a bone-thinning disorder associated with aging, heightening the risk of bone fractures. Bisphosphonates, such as denosumab (Prolia), alendronate (Fosamax), and risedronate (Actonel), inhibit the action of osteoclast cells to decrease bone turnover and increase bone mineral density (BMD). While these drugs are widely utilized and highly effective in reducing the risk of bone fractures, they are associated with serious adverse effects such as medication-related osteonecrosis of the jaw (MRONJ, a chronic condition that affects the oral cavity, leading to mucosal ulceration and refractory exposure of underlying necrotic bone), and atypical femur fracture (AFF, a fracture of the femoral shaft). These risks are associated with significant morbidity and mortality in some patients. Before prescribing medications with serious warnings, APRNs must ensure patients are fully educated on the possible complications to facilitate informed decision-making (Porter & Varacallo, 2020).

The Risk Evaluation and Mitigation Strategy (REMS) Program

Some drugs require strict monitoring as outlined by the FDA REMS program, which is reserved for drugs with serious safety concerns to help ensure the benefits of a medication choice outweigh the associated risks. REMS is designed to mitigate the occurrence and severity of certain risks by enhancing the safe use of high-risk medications, as described within the FDA-approved prescribing information. REMS programs heighten the monitoring and surveillance of patients receiving high-risk medications. REMS programs consist of information communicated to and/or required activities to be undertaken by one or more participants (e.g., healthcare providers, pharmacists, patients) who prescribe, dispense, or take the medication. Each REMS program addresses a specific safety concern related to the medication. While the requirements for each REMS program vary, most require prescribers to enroll in the program, complete the specified training, document patient counseling, enroll patients, monitor, and confirm compliance with the safe use of the medication (FDA, 2019a). Isotretinoin (Accutane) is used to treat severe acne; it carries an extremely high risk of congenital deformities if pregnancy occurs while taking the medication in any amount, even for a short period. Any fetus exposed during pregnancy could be affected. Due to the severity of this toxicity, isotretinoin (Accutane) can only be marketed under a restricted distribution REMS program called iPLEDGE. This specialized REMS program for isotretinoin (Accutane) aims to (a) prevent fetal exposure and (b) inform prescribers, pharmacists, and patients about its severe risks and safe-use conditions. Prescribers must be registered with and activated by the iPLEDGE program and can only prescribe isotretinoin (Accutane) to registered patients who meet all the requirements of iPLEDGE. Furthermore, the medication can be dispensed only by a pharmacy registered with and activated by the iPLEDGE program (FDA, 2018a). 

Boxed Warnings

The FDA requires boxed warnings for certain medications that carry severe safety risks. These warnings communicate the rare but potentially dangerous adverse effects of the drug and essential instructions for safe use. Boxed warnings typically appear in bold font on the medication. They are surrounded by a black border on the medication package insert and the drug manufacturer’s website (hence the moniker, black box warning), as demonstrated in Figure 10 (Katzung, 2018; FDA, 2020b).

In 2004, the FDA required a boxed warning on all antidepressant medications (e.g., SSRIs, SNRIs, etc.) regarding the risk of increased suicidality among children and adolescents taking these medications. A few years later, the warning was expanded to include all young adults, especially those under the age of 25, stating that these individuals may experience an increase in suicidal thoughts or behaviors during the first few weeks of taking an antidepressant and warning clinicians to monitor patients for this effect. Patients with underlying depression treated with SSRIs and SNRIs may experience worsening depression and/or the emergence of suicidal ideation and suicidality. This risk may persist until significant remission occurs. Research has demonstrated that SSRIs and SNRIs increase the risk of suicidality when compared to placebo controls. The FDA also requires manufacturers to provide a Patient Medication Guide (MedGuide), which is given to recipients of these medications to advise them of risks and precautions to reduce the risk for suicide. APRNs should inquire directly about suicidal thoughts before prescribing antidepressants to young persons. All patients treated with antidepressants (for any indication) should be counseled on the risk of increased suicidality and encouraged to monitor and report worsening symptoms, suicidality, and unusual changes in behavior, especially during the first few months of treatment. Table 6 provides the points that must be included in antidepressant boxed warnings (FDA, 2018b).

Contraindications

Some drugs are contraindicated in specific populations due to their potential to cause severe or life-threatening adverse effects. For example, acetylsalicylic acid (Aspirin) is contraindicated in children suffering from a viral infection due to the risk of Reye syndrome. Reye syndrome is a rare but serious condition that causes swelling in the liver and brain and most commonly affects children recovering from influenza or chickenpox (Katzung, 2018). Children under 8 years old should not be given tetracycline antibiotics (e.g., minocycline [Minocin], doxycycline [Monodox]) because they can permanently stain developing teeth (Shutter & Akhoni, 2021). APRNs should only consider using drugs in these situations under particular circumstances (Katzung, 2018). 

Pregnant and Lactating Women

Pregnant women have a high risk of maternal and fetal adverse drug effects, and extreme caution must be exercised before prescribing medications to these patients. Some drugs are teratogenic (i.e., can disturb the development of the embryo or fetus) and cause significant congenital disabilities if administered during pregnancy, typically during the first trimester (Katzung, 2018). For example, women with type 2 diabetes taking oral diabetic agents (e.g., glucophage [Metformin]) usually need to switch to insulin, as the safety of oral antihyperglycemics during pregnancy has not yet been established. Pregnancy-related insulin resistance also decreases the effectiveness of oral diabetic agents (American Diabetes Association, n.d.). 

Before 2015, pregnancy- and lactation-related drug risks were assigned categories of A, B, C, D, and X. These five categories indicated a drug’s risk of causing fetal injury when taken during pregnancy; however, they were often criticized for leading to prescribing errors based on false conclusions drawn from the categories. Effective June 30, 2015, the FDA replaced these categories with the Pregnancy and Lactation Labeling Rule (PLLR). The PLLR provides a concise, standardized summary of available evidence and detailed animal data on the medication, including a background risk statement and the estimated risk of significant congenital disabilities and miscarriage. APRNs should consistently reference the most recent, evidence-based drug resources before prescribing medications to pregnant patients (FDA, 2021, Pernia & DeMaagd, 2016).

Older Adults

The known physiological changes accompanying advancing age should be considered when prescribing medications to patients older than 65. Although most medications’ absorption rate does not change with age, common drugs can alter other medications’ absorption by this population. Furthermore, certain conditions may reduce the acidity of the GI tract or the availability of intrinsic factors, thereby interfering with proper medication absorption. The percentage of body fat typically increases with age, while the amount of total body water decreases. This gradual change can lead to longer half-lives for fat-soluble medications and an increase in the concentration of water-soluble medications. In addition, hepatic blood flow tends to decrease with age (along with size/mass), altering the body’s ability to process and clear drugs. Hepatic impairment may further increase a medication’s half-life and alter how frequently it should be dosed. Evaluating for these changes is especially crucial for patients taking medications that are processed via cytochrome P450. Patients with decreased hepatic metabolism who take medications processed via cytochrome P450 may experience higher circulating levels of medications, especially warfarin (Coumadin) and phenytoin (Dilantin; Saljoughian, 2019; Terrery & Nicoteri, 2016). 

Similarly, drug elimination can be impacted by renal impairments associated with advanced age, such as diminished renal blood flow, fewer functioning nephrons, decreased glomerular filtration rate, and tubular secretion. Like hepatic impairment, renal deficiency can also increase a medication’s half-life, shifting its dosing frequency. Reduced lean muscle mass can diminish CrCl, rendering this an inaccurate indicator of medication elimination. Several medications that rely heavily on renal excretion are commonly used for older adults, such as allopurinol (Aloprim), H2 blockers (e.g., ranitidine [Zantac] and famotidine [Pepcid]), digoxin (Lanoxin), lisinopril (Zestril, Prinivil), atenolol (Tenormin), ciprofloxacin (Cipro), lithium (Lithobid), vancomycin (Vancocin), amantadine (Symmetrel, Osmolex ER), and memantine (Namenda). See Table 7 for additional information regarding renal function considerations in prescribing. Increasing levels of unbound or free medication may result from a reduction in serum albumin levels related to malnutrition in a geriatric patient experiencing feeding or eating problems. Decreased cardiac output may lead to inadequate drug distribution (Saljoughian, 2019; Terrery & Nicoteri, 2016). Due to changes in pharmacodynamics in older adults, many patients will also develop a heightened sensitivity to certain drugs. Thus, a lower dosage of most medications may be required to achieve the same Cp and therapeutic effects (Rochon, 2020).

Various tools have been developed to help screen for potentially inappropriate medications (PIMs) in older adults. The American Geriatrics Society (AGS) Beers Criteria for Potentially Inappropriate Medication Use in Older Adults (The Beers Criteria, or BC) was last updated in 2019 and includes the following categories: PIMs, medications that are potentially inappropriate with certain conditions, medications that should be used with caution, drug-drug interactions that should be avoided, and medications that should be avoided or reduced in patients with kidney dysfunction (see Table 7). For example, drugs with substantial anticholinergic effects such as first-generation antihistamines (e.g., diphenhydramine [Benadryl], dimenhydrinate [Dramamine]) should be avoided due to the reduced renal clearance in older adults and risks of confusion, dry mouth, constipation, and other anticholinergic effects or toxicity. In addition, the use of meperidine (Demerol) is discouraged for this population since impaired renal function can lead to an accumulation of normeperidine, a neurotoxic metabolite (AGS Beers Criteria Update Expert Panel, 2019; Fixen, 2019; Nguyen et al., 2020).

Older Adults and Polypharmacy. Roughly one-half (44% of men and 57% of women) of those over 65 take at least five medications (prescription or OTC) every week. In this age group, 12% of patients take at least 10 medications. Polypharmacy (the simultaneous use of multiple medications) becomes an issue if it contributes to negative outcomes, such as adverse events, nonadherence, and increased cost (Saljoughian, 2019). For example, polypharmacy is established as an independent risk factor for hip fractures in older adults (Rochon, 2020). Being prescribed various medications by multiple providers increases the risk of adverse events and drug-drug interactions for older adults. Polypharmacy leads to therapeutic duplication, unnecessary medication use, increased side effects, and poor adherence. Risk factors for polypharmacy include advancing age, lack of education, ethnicity, health status, and access to a pharmacy (Nguyen et al. 2020; Ward & Reuben, 2020). A patient taking 5 to 9 different medications has a 50% chance of experiencing a drug-drug interaction, and that probability increases to 100% in a patient taking 20 or more medications. While polypharmacy increases the risk of poor adherence, geriatric patients may also have other issues specific to their population that affect compliance. These include forgetting to take their medications due to cognitive impairment, poor vision, limited financial resources, and limited access to or transportation to a pharmacy, all of which have been shown to reduce medication regimen adherence. A common phenomenon among older adults with multiple prescribed medications, a prescribing cascade, occurs when additional medications are prescribed due to the misdiagnosis of an adverse effect as a new medical condition. For example, many antipsychotic medications may lead to parkinsonism (symptoms that mimic Parkinson's disease in patients without the underlying diagnosis), prompting the prescription of an antiparkinsonian medication, which then causes orthostatic hypotension and delirium. APRNs must ensure that they consistently and accurately communicate all medication changes to the other members of the interdisciplinary healthcare team, including pharmacists, intensivists, specialists, and primary care providers (Rochon, 2020; Saljoughian, 2019).

For more information on older adults and polypharmacy, refer to the NursingCE course Care Considerations for Older Adults: The Assessment and Management of Polypharmacy for APRNs

Medication Errors

Attention toward medication errors has grown since 2000 when the Institute of Medicine (IOM), now called the National Academy of Medicine (NAM), released their landmark report, To Err Is Human. The report called to light the astronomical data surrounding medication errors as common, costly, and preventable medical mishaps, citing nearly 98,000 hospitalized patient deaths per year due to preventable medical errors. This momentous study ignited a focus on medical practices, spawning new policies and procedures and setting performance standards and expectations for patient safety and quality improvement (IOM US Committee on Quality of Health Care in America, 2000). In a 2007 report entitled Preventing Medication Errors, the IOM released alarming statistics that more than 1.5 million people suffered an injury each year in US hospitals; the average hospitalized patient experienced at least one medication error daily (IOM, 2007). In a 2016 study by Johns Hopkins University, researchers compared medical errors to the annual list from the CDC of the most common causes of death in the US. Their findings demonstrated that 10% of all deaths in the US are attributable to medical errors, branding medical errors as the third-highest cause of death (Makary & Daniel, 2016). To date, the FDA (2019b) receives at least 100,000 reports annually associated with a suspected medication error. Each year, up to 9,000 people die due to a medication error (Tariq et al., 2021). Safe medication administration involves the entire healthcare team and carries legal and ethical implications. The primary focus of effective medication administration is patient safety. Although many measures have been employed over the past few decades to promote and enhance patient safety, medication errors and adverse drug events (ADEs) continue to occur. ADEs are temporally associated with the use of a drug but not necessarily causally related. ADE encompasses all drug-related incidents, including adverse reactions and medication errors. The World Health Organization (WHO) estimates that the global cost associated with medication errors is $42 billion annually (WHO, n.d.).

According to the AHRQ (2019), a medication error is a preventable event defined as "an error (of commission or omission) at any step along the pathway that begins when a clinician prescribes a medication and ends when the patient receives the medication." ADEs account for nearly 700,000 emergency department visits and 100,000 hospitalizations each year. Almost 5% of hospitalized patients experience an ADE, making them a prevalent inpatient medical error (AHRQ, 2019). Incorporating the NAM competencies for nursing, the Quality and Safety Education for Nurses (QSEN) framework identified the following six competencies necessary for safe practice: patient-centered care, teamwork and collaboration, evidence-based practice, quality improvement, safety, and informatics. Nursing programs are tasked with integrating these principles into their curricula to support safe medication administration (QSEN, 2020). As part of their national patient safety goals (NPSG), The Joint Commission (TJC) has identified particular areas of interest regarding medication administration; one such area addresses errors that occur when reading and interpreting new medication orders. A "Do Not Use" list of abbreviations has been established to avert confusion that could lead to a medication error, as summarized in Figure 11 (TJC, 2020, 2021a, 2021b).

Figure 11

Official "Do Not Use" List

Appropriate medication labeling and use of anticoagulant medications have also been implemented to reduce the likelihood of patient harm. The 2021 version of the TJC NPSG incorporates medication reconciliation in response to the large percentage of patients taking multiple medications and the complexity of managing them (see Table 8). Medication reconciliation is the process of directly comparing the medications a patient is prescribed with newly ordered medications and is intended to identify and resolve discrepancies; it addresses duplications, omissions, and interactions. The medication list must include the drug name, dosage, frequency, and route. Potential errors during medication reconciliation include omitting a medication, recording the drug more than once, or recording an incorrect dose or frequency (Institute for Healthcare Improvement, n.d.; TJC, 2021a, 2021b).

The FDA and the Institute for Safe Medication Practices (ISMP) collaboratively generated a list of high-alert medications that pose an enhanced risk of causing significant patient harm if given inappropriately. The ISMP Look-Alike/Sound-Alike (LASA) medication list refers to visually similar drugs (i.e., physical appearance or packaging) and names of medications with similar spelling or phonetics. Tall man lettering (TML) is a technique that uses uppercase lettering to help differentiate look-alike drug names. TML distinguishes between similar drug names by capitalizing dissimilar letters (see Table 9). TML is often used alongside color changes or bold-style font to draw attention to the dissimilarities between look-alike drug names and alert healthcare professionals that the drug name is easily confused with another (FDA, 2020a; ISMP, 2016).

American Nurses Association (ANA) Code of Ethics

The ANA’s Code of Ethics serves as a guide for implementing nursing responsibilities consistent with quality in nursing care and ethical obligations. Several of the provisions cited within the document influence how nurses should ethically administer medications. The following points summarize how each provision affects medication administration (ANA, 2015; Ernstmeyer & Christman, 2020):

• Provision 1 focuses on respect for human dignity and the right to self-determination, instructing nurses to deliver care with compassion and respect for each patient's dignity, worth, and unique attributes.
• Provision 2 denotes that each nurse’s primary commitment is to the patient, embracing the patient’s right to accept, refuse, or terminate any treatment, including medications.
• Provision 3 refers to a nurse’s responsibility in promoting, advocating for, and protecting each patient's rights, health, and safety, upholding a culture of safety. If medication errors occur, a nurse must report them and ensure the responsible disclosure of errors to patients, including an appropriate disclosure of any questionable practices, such as drug diversion or impaired practice by any healthcare professional or colleague.
• Provision 4 refers to a nurse’s authority, accountability, and responsibility to follow and carry out all legal requirements, such as state practice acts and professional standards of care.
• Provision 5 involves a nurse’s responsibility to promote health and safety.
• Provision 6 identifies a nurse’s morals and virtues, such as their accountability to exercise clinical judgment to avoid causing harm to patients (maleficence) and do good (beneficence) when administering medications and caring for patients.
• Provision 7 refers to a nurse’s responsibility of practicing within the professional standards set forth by their state nurse practice act and standards established by professional nursing organizations.
• Provision 8 focuses on a nurse’s role in addressing the social determinants of health, such as poverty, education, safe medication use, and healthcare disparities.

APRN Responsibilities in Preventing Medication Errors

APRNs must assess a patient's condition before prescribing the medication and anticipate possible side effects, interactions, contraindications, and precautions. Various sources refer to the 5 rights of medication administration, and some list up to 10 rights of medication administration (see Table 10; AHRQ, 2019; Hanson & Haddad, 2020; Katzung, 2018). 

Medication errors can occur from the time a healthcare provider writes the prescription to the pharmacy filling the drug to the actual delivery of medication to the patient, and the entire interdisciplinary team is responsible for promoting safe medication administration. Mistakes can occur at various steps in the medication administration process, but following the steps consistently can reduce or avoid costly errors. The appropriate medication, route, dose, and duration should be selected. APRNs should note that while EHRs have improved prescribing safety by alerting the user when a medication incompatibility is detected, an overabundance of these reminders can lead to reminder fatigue (also called alert or alarm fatigue). Table 11 summarizes the primary APRN responsibilities regarding preventing medication errors (AHRQ, 2019; Burcham & Rosenthal, 2019; Katzung, 2018; Saljoughian, 2019).

Key Takeaways

APRNs must be knowledgeable of all drugs they prescribe to patients. Understanding the pharmacokinetics and pharmacodynamics of a drug is vital for safely administering the drug while monitoring for adverse drug effects, signs of an HSR, and toxicity. Patient characteristics such as age, health alterations, and liver or kidney impairment must also be considered. APRNs must recognize which medications require peak and trough level monitoring and ensure they are ordered and performed as directed. APRNs should routinely and meticulously review all drugs prescribed to a patient to ensure accuracy, safety, and avert drug interactions. APRNs are responsible for safeguarding patient care by serving as each patient’s advocate. Education and proper communication can help avoid many medication errors and adverse effects. Patients should be encouraged to maintain an accurate medication list; they should update it regularly, bring it with them to all medical appointments (or keep a digital copy on their phone), and share it with all of their medical providers to ensure accuracy and awareness across disciplines and specialists. APRNs should educate patients and caregivers on any new medications, the rationale for use, possible side effects, and any dietary restrictions, as well as alert them to LASA medications to avoid dosing errors at home. Patients should be encouraged not to stop or change how they take a medication without discussing this action with the prescriber first. Patients should be directly asked at each visit about medication adherence. Education about medication safety can also prevent mishaps, including not saving or sharing medications and storing medication in a secure location. For older adults or patients with memory deficits, APRNs should encourage them to explore various solutions available, such as pill dispensers, color-coded pillboxes, or technology aids offering reminder features, such as smartphone applications. A simple alternative is to link the medication dose with routine daily activity, such as brushing their teeth, shaving, or drinking coffee (Katzung, 2018; Saljoughian, 2019). 

For more information on medication errors and medical errors, refer to the Medical Errors NursingCE Course.

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